Method and system for monitoring and controlling systemic and pulmonary circulation during a medical procedure

ABSTRACT

A method of performing a medical procedure, such as surgery, is provided. The system comprises a sensor to sense a biological characteristic, such as a chemical, physical or physiological characteristic of a bodily tissue or fluid. The method also comprises a nerve stimulator in communication with the sensor to inhibit beating of a heart when the sensor senses the biological characteristic at a first value; and a cardiac stimulator in communication with the sensor to stimulate beating of the heart when the sensor senses the biological characteristic at a second value.

PRIORITY

Applicants claim priority to co-pending U.S. patent application Ser. No.09/669,961 filed Sep. 26, 2000.

FIELD OF THE INVENTION

This invention relates to methods and systems for performing a medicalprocedure, especially procedures during which it is necessary to adjustthe beating of the heart in order to allow the medical procedure to beperformed on the heart or another organ. More particularly, thisinvention relates to methods and systems for monitoring and controllingone or more physiological and/or chemical parameters of a fluid such asblood or oxygen in the systemic and/or pulmonary circulatory systemsduring such a medical procedure.

BACKGROUND OF THE INVENTION

The current leading cause of death in the United States is coronaryartery disease in which the coronary arteries are blocked byatherosclerotic plaques or deposits of fat. The typical treatment torelieve a partially or fully blocked coronary artery is coronary arterybypass graph (CABG) surgery.

CABG surgery, also known as “heart bypass” surgery, generally entailsusing a graph to bypass the coronary obstruction. The procedure isgenerally lengthy, traumatic and subject to patient risks. Among therisk factors involved is the use of a cardiopulmonary bypass (CPB)circuit, also known as a “heart-lung machine”, to pump blood andoxygenate the blood so that the patients heart may be stopped during thesurgery.

Conventional CABG procedures are typically conducted on a stopped heartwhile the patient is on a (CPB) circuit. A stopped heart and a CPBcircuit enables a surgeon to work in a bloodless, still operative field.However, there a number of problems associated with CABG proceduresperformed while on CPB including the initiation of a systemicinflammatory response due to interactions of blood elements with theartificial material surfaces of the CPB circuit and global myocardialischemia due to cardioplegic cardiac arrest. For these reasons, avoidingthe use of CPB or cardioplegic cardiac arrest may help minimizepost-operative complications.

One method, as disclosed in U.S. Pat. No. 5,651,378 to Matheny andTaylor and in U.S. Pat. No. 5,913,876 to Taylor et al., for facilitatingcoronary bypass surgery on a beating heart and thereby avoid the use ofCPB and cardioplegic cardiac arrest includes stimulating the vagal nerveelectrically in order to temporarily stop or substantially reduce thebeating of the heart. This may be followed by pacing the heart to startits beating.

Another method, as disclosed in two published PCT applications, WO99/09971 and WO 99/09973, both to Puskas, involves stopping the beatingof the heart during coronary bypass surgery using electrical stimulationof the vagal nerve in combination with administration of drugs. Anothermethod, as disclosed in U.S. Pat. No. 6,060,454 to Duhaylongsod,involves stopping the beating of the heart during coronary bypasssurgery via the local delivery of drugs to the heart.

Although it is desirable to stop the heart for a period of time in orderto allow the surgeon to accomplish a required task without interferencefrom heart movement, i.e. a motionless operative field, it isundesirable to have the heart stopped for too long a period of timesince the body needs, among other things, constant supply of oxygen. Infact it is particularly important to maintain sufficient blood flow, andtherefore oxygen flow, to the brain. A system for sensing biologicalparameters, such as the amount of blood flow or oxygen flow to thebrain, could help determine whether these parameters are sufficientduring a medical procedure.

It would be desirable to provide a method for controllably stopping orslowing the heart intermittently in order to control blood flow in thesystemic and/or pulmonary circulatory systems during a medicalprocedure.

Additionally, it would be desirable to provide a means for monitoringone or more chemical, physical or physiological characteristics of abodily tissue or fluid during the procedure.

Additionally, it would be desirable to provide a method for controllablystopping or slowing the heart intermittently for diagnostic ortherapeutic purposes.

Additionally, it would, be desirable to provide a method forcontrollably stopping or slowing the heart intermittently in order toperform surgery on the heart or another organ.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a system for performing amedical procedure. The system includes a sensor to sense a biologicalcharacteristic, a nerve stimulator to inhibit beating of a heart whenthe sensor senses the biological characteristic at a first value and acardiac stimulator to stimulate beating of the heart when the sensorsenses the biological characteristic at a second value.

The biological characteristic maybe a chemical characteristic of atissue, a chemical characteristic of a fluid, a physical characteristicof a tissue, a physical characteristic of a fluid, a physiologicalcharacteristic of a tissue, and a physiological characteristic of afluid. The biological characteristic may be a characteristic of a bodycomponent such as the blood, blood, cardiac tissue, or a nerve. Thebiological characteristic may be fluid flow, fluid pressure, mechanicalpressure, temperature, electrical current, chemical concentration,presence of a protein, concentration of a protein, presence of apeptide, concentration of a peptide, a metabolic process, presence of agas, concentration of a gas, presence of oxygen, concentration ofoxygen, presence of carbon dioxide, concentration of carbon dioxide.

The system may also include drug delivery means such as a spray, acream, an ointment, a medicament, a pill, a patch, a catheter, acannula, a needle and syringe, a pump, and an iontophoretic drugdelivery device to deliver at least one drug during the procedure. Thedrug may be a beta-blocker, a cholinergic agent, a cholinesteraseinhibitor, a calcium channel blocker, a sodium, channel blocker, apotassium channel agent, adenosine, an adenosine, receptor agonist, anadenosine deaminase inhibitor, dipyridamole, a monoamine oxidaseinhibitor, digoxin, digitalis, lignocaine, a bradykinin agent, aserotoninergic agonist, an antiarrythmic agent, a cardiac glycoside, alocal anesthetic, atropine, a calcium solution, an agent that promotesheart rate, an agent that promotes heart contractions, dopamine, acatecholamine, an inotrope glucagon, a hormoone, forskolin, epinephrine,norepinephrine, thyroid hormone, a phosphodiesterase inhibitorprostacyclin, prostagiandin and a methylxanthine. The drug may benaturally occurring or chemically syrithesized.

The nerve stimulator may stimulate a nerve such as a vagal nerve, acarotid sinus nerve, a fat pad. The nerve stimulation may be stoppedautomatically when the sensor senses the biblogical characteristic atthe second value. Cardiac stimulation may begin automatically when thesensor senses the biological characteristic at the second value. Thenerve stimulator may be, for example, one or more electrodes, such asnerve stimulation electrodes, endotracheal electrodes, endoesophagealelectrodes, intravascular electrodes, transcutaneous electrodes,intracutaneous electrodes, balloon-type electrodes, basket-typeelectrodes, umbrella-type electrodes, tape-type electrodes, suction-typeelectrodes, screw-type electrodes, barb-type electrodes, bipolarelectrodes, monopolar electrodes, metal electrodes, wire electrodes,patch electrodes, cuff electrodes, clip electrodes, needle electrodesand probe electrodes.

The sensor may be an imaging system, an electrical sensor, a chemicalsensor, an electromagnetic interference sensor, an electrochemicalsensor, a pressure sensor, a sound wave sensor, a magnetic sensor, anultraviolet sensor, a visible light sensor, an infrared sensor, aradiation sensor, a flow sensor, a temperature sensor, a gas sensor, anoptical sensor, a pH sensor, a potentiometric sensor, a fluorescencesensor and a biosensor.

The cardiac stimulator may be, for example, one or more electrodes, suchas cardiac stimulation electrodes, clip electrodes, needle electrodes,probe electrodes, pacing electrodes, epicardial electrodes, patchelectrode intravascular electrodes, balloon-type electrodes basket-typeelectrodes, tape-type electrodes, umbrella type electrodes, suction-typeelectrodes, endotracheal electrodes, endoesophageal electrodes,transcutaneous electrodes, intracutaneous electrodes, screw-typeelectrodes, barb-type electrodes, bipolar electrodes, monopolarelectrodes, metal electrodes, wire electrodes and cuff electrodes.

The system may also include a breathing regulator, which may control arespirator. The breathing regulator may stimulate a phrenic nerve. Thebreathing regulator may be, for example, one or more electrodes such asnerve stimulation electrodes, endotracheal electrodes, endoesophagealelectrodes, intravascular electrodes, transcutaneous electrodes,intracutaneous electrodes, balloon-type electrodes, basket-typeelectrodes, umbrella-type electrodes, suction-type electrodes,screw-type electrodes, tape-type electrodes, barb-type electrodes,bipolar electrodes, monopolar electrodes, metal electrodes,wire-electrodes, patch electrodes, cuff electrodes, clip electrodes,needle electrodes and probe electrodes.

The medical procedure may be a surgical procedure, a non-surgicalprocedures, a fluoroscopic procedure, a cardiac procedure, a vascularprocedure, a neurosurgical procedure, an electrophysiological procedure,a diagnostic procedure, a therapeutic procedure, an ablation procedure,an endovascular procedure, a liver procedure, a spleen procedure, apulmonary procedure, an aneurysm repair, an imaging procedure, a CATscan procedure, a MRI procedure, a pharmacological therapy, a drugdelivery procedure, a biological delivery procedure, a genetic therapy,a cellular therapy, a cancer therapy, a radiation therapy, atransplantation procedure, a coronary angioplasty procedure, a stentdelivery procedure, an atherectomy procedure, a procedure that requiresprecise control of cardiac motion, a procedure that requires precisecontrol of bleeding, a non-invasive procedure, a minimally invasiveprocedure, an invasive procedure, a port-access procedure, an endoscopicprocedure, a sternotomy procedure, a thoracotomy procedure and a roboticprocedure.

Another aspect of the present invention provides a method for performinga medical procedure. A biological characteristic is sensed at a firstvalue and a first signal related to the sensed biological characteristicis sent. Beating of a heart is inhibited in response to the firstsignal. The medical procedure is then performed. The biologicalcharacteristic is then sensed at a second value and a second signalrelated to the sensed biological characteristic at the second value issent. Beating of the heart is stimulated in response to the secondsignal.

Beating of the heart may be inhibited automatically in response to thefirst signal. Beating of the heart may be stimulated automatically inresponse to the second signal. At last one drug may be delivered duringthe medical procedure. A nerve may be stimulated to inhibit beating ofthe heart. Breathing may be stopped while beating of the heart isinhibited. Breathing may be stopped automatically.

The biological characteristic may be a characteristic of blood, acharacteristic of cardiac tissue, a characteristic of a nerve, a fluidflow characteristic, a pressure characteristic, a temperaturecharacteristic, an electrical characteristic, a chemical concentration,a presence of a protein, a concentration of a protein, a presence of apeptide, a component of a metabolic process, a presence of a gas, aconcentration of a gas, a presence of oxygen, a concentration of oxygen,a presence of carbon dioxide, a concentration of carbon dioxide, achemical characteristic, a physical characteristic, and a physiologicalcharacteristic.

Another aspect of the present invention provides a device for performinga medical procedure. The device includes a processor, a sensor to sensea biological characteristic and at least one nerve stimulationelectrode. The processor receives a signal from the sensor and adjustsoutput from the nerve stimulation electrode in response to the signal.

The sensor may be an imaging system, an electrical sensor, a chemicalsensor, an electromagnetic interference sensor, an electrochemicalsensor, a pressure sensor, a sound wave sensor, a magnetic sensor, anultraviolet sensor, a visible light sensor, an infrared sensor, aradiation sensor, a flow sensor, a temperature sensor, a gas sensor, anoptical sensor, a pH sensor, a potentiometric sensor, a fluorescencesensor and a biosensor.

The nerve stimulation electrode may be one or more electrodes, such asendotracheal electrodes, endoesophageal electrodes, intravascularelectrodes, transcutaneous electrodes, intracutaneous electrodes,balloon-type electrodes, basket-type electrodes, umbrella-typeelectrodes, tape-type electrodes, suction-type electrodes, screw-typeelectrodes, barb-type electrodes, bipolar electrodes, monopolarelectrodes, metal electrodes, wire electrodes, patch electrodes, cuffelectrodes, clip electrodes, needle electrodes and probe electrodes.

The device may also include a cardiac stimulation electrode to stimulatebeating of the heart. The processor receives a signal from the sensorand adjusts output from the cardiac stimulation electrode in response tothe signal. The cardiac electrode may be, for example, one or moreelectrodes such as clip electrodes, needle electrodes, probe electrodes,pacing electrodes, epicardial electrodes, patch electrodes,intravascular electrodes, balloon-type electrodes, basket-typeelectrodes, tape-type electrodes, umbrella-type electrodes, suction-typeelectrodes, endotracheal electrodes, endoesophageal electrodes,transcutaneous electrodes, intracutaneous electrodes, screw-typeelectrodes, barb-type electrodes bipolar electrodes, monopolarelectrodes, metal electrodes, wire electrodes and cuff electrodes.

The device may also include a breathing regulation electrode forcontrolling breathing. The processor adjusts the output from thebreathing regulation electrode in response to the signal. The breathingregulation electrode may be, for example, one or more electrodes such asnerve stimulation electrodes, endotracheal electrodes, endoesophagealelectrodes, intravascular electrodes, transcutaneous electrodes,intracutaneous electrodes, balloon-type electrodes; basket-typeelectrodes, umbrella-type electrodes, suction-type electrodes,screw-type electrodes, tape-type electrodes, barb-type electrodes,bipolar electrodes, monopolar electrodes, metal electrodes, wireelectrodes, patch electrodes, cuff electrodes; clip electrodes, needleelectrodes and probe electrodes.

The device may also include a drug pump for delivering at least onedrug. The processor adjusts the output of the drug. The drug may be, forexample, a beta-blocker, a cholinergic agent, a cholinesteraseinhibitor, a calcium channel blocker, a sodium channel-blocker, apotassium channel agent, adenosine, an adenosine receptor agonist, anadenosine deamrinase inhibitor, dipyridamole, a monoamine oxidaseinhibitor, digoxin, digitalis, lignocaine, a bradykinin agent, aserotoninergic agonist, an antiarrythmic agent, a cardiac glycoside, alocal anesthetic, atropine, a calcium solution, an agent that promotesheart rate, an, agent that promotes heart contractions, dopamine,catecholamine, an inotrope glucagon, a hormone, forskolin, epinephrinenorepinephrine, thyroid hormone, a phosphodiesterase inhibitor,prostacyclin, prostaglandin and a methylxanthine.

The foregoing, and other, features and advantages of the invention willbecome further apparent from the following detailed description of thepresently preferred embodiments, read in conjunction with theaccompanying drawings. The detailed description and drawings are merelyillustrative of the invention rather than limiting, the scope of theinvention being defined by the appended claims in equivalence thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of one embodiment of a system for monitoringat least one chemical, physical or physiological characteristic during amedical procedure in accordance with the present invention;

FIG. 2 is a schematic view of one embodiment of a medical device inaccordance with the present invention;

FIG. 3 is a flow diagram of one embodiment of a method of performing amedical procedure in accordance with the present invention; and

FIG. 4 is a timeline view of one embodiment of a system for monitoringat least one chemical, physical or physiological characteristic during amedical procedure in accordance with the present invention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

FIG. 1 shows a schematic view of one embodiment of a system forperforming a medical procedure in accordance with the present inventionat 100. System 100 comprises a sensor 5, a nerve stimulator 10, and acardiac stimulator 20. System 100 may also feature a controller 30 and abreathing regulator 40.

Sensor 5 may be any suitable blood gas sensor for measuring theconcentration or saturation of a gas in the blood stream. For example,sensor 5 may be a sensor for measuring the concentration or saturationof oxygen or carbon dioxide in the blood. Alternatively, sensor 5 may beany suitable sensor for measuring blood pressure or flow, for example aDoppler ultrasound sensor system, or a sensor for measuring hematocrit(HCT) levels.

Alternatively sensor 5 may be a biosensor, for example, comprising anImmobilized biocatalyst, enzyme, immunoglobulin, bacterial, mammalian orplant tissue, cell and/or subcellular fraction of a cell. For example,the tip of a biosensor may comprise a mitochondrial fraction of a cell,thereby providing the sensor with a specific biocatalytic activity.

Sensor 5 may be based on potentiometric technology or fiber optictechnology. For example, the sensor may comprise a potentiometric orfiber optic transducer. An optical sensor may be based on either anabsorbance or fluorescence measurement and may include an UV, a visibleor an IR light source.

Sensor 5 may be used to detect naturally detectable propertiesrepresentative of one or more characteristics, e.g., chemical, physicalor physiological, of a patients bodily tissues or fluids. For example,naturally detectable properties of patients bodily tissues or fluids mayinclude pH, fluid, flow, electrical current, temperature pressure,components of metabolic processes, chemical concentrations, for example,the absence or presence of specific peptides, proteins, enzymes, gases,ions, etc.

Sensor 5 may include one or more imaging systems, camera systemsoperating in UV, visible, or IR range; electrical sensors; voltagesensors; current sensors; piezoelectric sensors; electromagneticinterference (EMI) sensors; photographic plates, polymer-metal sensors;charge-coupled devices (CCDs); photo diode arrays; chemical sensors,electrochemical sensors; pressure sensors, sound wave sensors; magneticsensors; UV light sensors; visible light sensors; IR light sensors;radiation sensors; flow sensors; temperature sensors; or any otherappropriate or suitable sensor. Sensor 5 may be a continuous, in-linemonitoring system or it may be attached to an extracorporeal device.

In one embodiment of the invention, sensor 5 may be a cerebral bloodflow sensor, in which case, the sensor may be placed in any suitablemanner for sensing cerebral blood flow. For example, sensor 5 may beinserted between the skull and the dura of the brain. Alternatively,sensor 5 may be placed in the patients neck. For example, at least aportion of sensor 5 may be placed in an artery, such as the carotidartery. Such a placement would allow measurement of blood as it flows tothe brain. Alternatively, sensor 5 may be placed in a vein, such as thejugular vein. This placement would allow measurement of blood as itflows from the brain.

In the case of blood oxygen saturation sensing, a certain level ofoxygen generally remains in the blood as it flows from the brain. Thislevel may be established by measuring the patients oxygen prior tosurgery. If blood measured by sensor 5 in the vein has oxygen below theestablished level, the brain is consuming all or most of the oxygenflowing to it and probably requires additional oxygen. Other suitableplacements of sensor 5 may be possible. Sensor 5 may be used to alert asurgeon to changes in the patients circulatory, system.

System 100 may also include a nerve stimulator 10. In one embodiment,the nerve stimulator 10 may be used to electrically manipulate cardiacrhythm by stimulating the vagus nerve. This vagal stimulation mayproduce asystole (slowing or stopping of the hearts beating.) Once thisinduced asystole is stopped, i.e. once the vagal stimulation is stopped,the heart may be allowed to return to its usual cardiac rhythm.Alternatively, the heart may be paced with an electrical pacing system,thereby maintaining a normal cardiaic output. Vagal stimulation, aloneor in combination with electrical pacing, may be used selectively andintermittently to allow a surgeon to perform a medical procedure duringintermittent periods of asystole.

It is known that stimulation of the vagus nerve can reduce the sinusrate, as well as prolong AV conduction time or if stimulation energiesare high enough, induce AV node block. Use of vagal nerve stimulation totreat supraventricular arrhythmias and angina pectoris is disclosed inthe article “Vagal Tuning” by Bilgutay et al., Journal of Thoracic andCardiovascular Surgery, Vol. 56, No. 1, July, 1968, pp. 71-82. It isalso known that stimulation of the carotid sinus nerve produces asimilar result, as disclosed in the article “Carotid Sinus NerveStimulation in the Treatment of Angina. Pectoris and SupraventricularTachycardia” by Braunwald et al., published in California Medicine, Vol.112, pp. 41-50, March, 1970.

As set forth in “Functional Anatomy of the Cardiac Efferent Innervation”by Randall et al., in Neurocardiology, edited by Kulbertus et al, FuturaPublishing Co., 1988, direct surgical excision of the fat pad associatedwith the SA node affects the functioning of the SA node withoutSignificantly affecting the AV node. Similarly, excision of the fat padassociated with the AV node affects functioning of the AV node withoutsignificantly affecting the SA node.

As set forth in the article “Parasympathetic Postganglionic Pathways tothe Sinoatrial Node”, Bluemel et al., Am. J. Physiol. 259, (Heart Circ.Physiol. 28). H1504-H1511, 1990, stimulation of the fat pad associatedwith the SA node results in slowing of the sinus rate without theaccompanying prolongation of AV conduction time which normally resultsfrom vagal nerve stimulation. The article also indicates thatstimulation of the fat pad associated with the AV node is believed toproduce corresponding effects limited to the AV node, i.e., extension ofthe AV conduction time without concurrent slowing of the sinus rate.

As set forth in the article “Neural Effects on Sinus Rate and AtrialVentricular Conduction Produced by Electrical Stimulation From aTransvenous Electrode Catheter in the Canine Right Pulmonary Artery” byCooper et al., published in Circulation Research, Vol. 46, No. 1,January, 1980, pp. 48-57, the fat pads associated with both the AV nodeand the SA node may be stimulated by means of electrodes located in theright pulmonary artery. The results obtained include-both a depressionof the sinus rate and a prolongation of the AV conduction time inresponse to continuous stimulation at 2-80 Hz at up to 50 ma.

Generally in healthy individuals, the SA node functions as thepacemaker. Normal heart rhythm associated with the SA node is typicallyreferred to as sinus rhythm. When the SA node fails, the AV nodegenerally takes over creating a heart rate of approximately 35 to 60beats per minute. Heart rhythm associated with the AV node is typicallyreferred to as nodal rhythm. When the AV node itself is blocked orinjured, a new seven slower pacemaker site may form at the junction ofthe AV node and the His bundle. Heart rhythm associated with thisjunction is typically referred to as junctional, escape rhythm. Whenthis junction site is inhibited, the Purkinje fibers in the His bundleor below may act as a pacemaker creating a heart rate of approximately30 beats per minute. Heart rhythm associated with the Purkinje fibers istypically referred to as idioventricular rhythm.

In one embodiment of the present invention, nerve stimulator 10 may beused to electrically manipulate cardiac rhythm by stimulating thecarotid sinus nerve, the fat pad associated with the SA node, the fatpad associated with the AV node, the junction of the AV node and the Hisbundle and/or the Purkinje fibers.

In one embodiment of the present invention, nerve stimulator 10 is usedalone or in combination with other heart rate inhibiting agents totemporarily stop or slow the beating heart, thereby eliminating orreducing heart motion and/or blood flow during a medical procedure. Forexample, the present invention may be used to eliminate or reduce motionin the anastomosis field during CABG Procedures such that a facilitatedanastomosis procedure may be performed; safely and effectively. Thenumber of occasions that the vagal nerve may be stimulated depends onthe type of medical procedure to be performed. Likewise, the type ofmedical procedure to be performed will dictate the duration of theindividual electrical stimulations.

Nerve stimulator 10 may be powered by AC current, DC current or it maybe battery powered either by a disposable or rechargeable battery. Nervestimulator 10 may be configured to synchronize activation anddeactivation of breathing regulator 40 with vagal stimulation, therebyminimizing or eliminating unwanted heart and chest motion associatedwith the patients breathing. Nerve stimulator 10 may comprise a surgeoncontrolled switch box. A switch may be incorporated in or on one of thesurgeons instruments, such as surgical site retractor, or any otherlocation easily and quickly accessed by the surgeon for regulation ofthe nerve stimulator by the surgeon. The switch may be, for example, ahand switch, a footswitch, or a voice-activated switch comprisingvoice-recognition technologies.

A visual and/or audible signal used to alert a surgeon to the completionor resumption of vagal nerve stimulation may be incorporated into nervestimulator 10. For example, a beeping tone or flashing light thatincreases in frequency as the nerve stimulation period should end orbegin may be used.

Nerve stimulator 10 may be slaved to cardiac stimulator 20 or cardiacstimulator 20 may be slaved to nerve-stimulator 10. For example, theoutput of cardiac stimulator 20 may be off whenever the output of nervestimulator 10 is on. Software controlling cardiac stimulator 20 may bedesigned to automatically commence cardiac pacing if the heart does notresume beating within a pre-determined interval after cessation of vagalnerve stimulation. In addition, the software controlling nervestimulator 10 may be designed to automatically stop vagal nervestimulation if the heart has been stopped for to long. For example, apredetermined time interval may be set to automatically stop vagalstimulation. In one embodiment of the invention, if sensor 5 of thepresent invention indicates that not enough blood is flowing to thebrain, vagal stimulation may be stopped, thereby allowing the heart tobeat again.

In another embodiment it may be necessary to use cardiac stimulator 20to actively stimulate the heart into beating again. For example in oneembodiment of the present invention, sensor 5 may indicate that notenough, blood is flowing to the brain causing nerve stimulator 10 to beautomatically turned off and cardiac stimulator 20 to be automaticallyturned on. Alternatively, the surgeon may turn on cardiac stimulator 20to begin stimulation.

Just like nerve stimulator 10, cardiac stimulator 20 may beintermittently stopped and, started to allows the surgeon to performindividual steps of a medical procedure.

Cardiac stimulator 20 may be a conventional ventricular demand pacer ordual chamber (atrial-ventricular) pacer. Cardiac stimulator 20 may bepowered by AC current, DC current or it may be battery powered either bya disposable or re-chargeable battery. Cardiac stimulator 20 may beconfigured to synchronize activation and deactivation of breathingregulator 40 with pacing, thereby minimizing or eliminating unwantedheart and chest motion associated with the patients breathing.

Cardiac stimulator 20 may be any conventional pacing device suitable forventricular demand pacing and having leads electrically coupled to aswitch box. Cardiac stimulator 20 may be combined in a single unit witha switch box. A switch may be incorporated in or on one of the surgeon'sinstruments, such as surgical site retractor, or any other locationeasily and quickly accessed by the surgeon for regulation of the cardiacstimulator by the surgeon. The switch may be, for example, a handswitch, a foot-switch, or a voice-activated switch comprisingvoice-recognition technologies. A single switch may be used to regulateboth cardiac stimulator 20 and nerve stimulator 10.

A visual and/or audible signal used to prepare a surgeon for theresumption of pacing may be incorporated into cardiac stimulator 20. Forexample, a beeping tone or flashing light that increases in frequency asthe pacing period ends may be used. A single signaling method or devicemay be used for both cardiac stimulator 20 and nerve stimulator 10.

Sensor 5, nerve stimulator 10 and/or cardiac stimulator 20 may be slavedto a robotic system or a robotic system may be slaved to sensor 5, nervestimulator 10 and/or cardiac stimulator 20. Breathing regulator 40 andother components may also be slaved to such a system. Computer andvoice-controlled robotic systems that position and maneuver endoscopesand/or other surgical instruments for performing microsurgicalprocedures such as anastomoses through small incisions may be used by asurgeon to perform precise and delicate maneuvers. These robotic systemsmay allow a surgeon to perform a variety of microsurgicalprocedures-including endoscopic CABG. Endoscopic CABG may allow multipleoccluded coronary arteries to be bypassed without a thoracotomy ormini-thoracotomy. Heart valve repair and replacement may also be othersurgical applications for these robotic systems. In general, roboticsystems may include head-mounted displays, which integrate 3-Dvisualization of surgical anatomy and related diagnostic and monitoringdata, miniature high resolution 2-D and 3-D digital cameras, a computer,a high power light source and a standard video monitor.

System 100 may also include a breathing regulator 40. In one embodiment,the breathing regulator 40 may be used to stimulate the phrenic nerve inorder to provide a diaphragmatic pacemaker. Breathing regulator 40 maycomprise one or more electrodes for supplying electrical current to thephrenic nerve to control breathing during vagal and/or cardiacstimulation and/or destimulation. Electrodes used to stimulate thephrenic nerve may be, for example, non-invasive, e.g., clips, orinvasive, e.g., needles or probes. The application of an electricalstimulus to the phrenic nerve may include, but is not limited to bipolarand/or monopolar techniques. Different electrode positions areaccessible through various access openings, for example, in the cervicalor thorax regions. Nerve stimulation electrodes may be positionedthrough a thoracotomy, sternotomy, endoscopically through a percutaneousport, through a stab wound or puncture, through a small incision, placedon the skin or in combinations thereof. The present invention mayinclude various electrodes, catheters and electrode catheters suitablefor phrenic nerve stimulation to control breathing.

Phrenic nerve stimulation electrodes may be intravascular, patch-type,balloon-type, basket-type, umbrella-type, tape-type, cuff-type,suction-type, screwy-type, barb-type, bipolar, monopolar, metal, wire,endotracheal, endoesophageal intravascular, transcutaneous orintracutaneous electrodes. Guided or steerable catheter devicescomprising electrodes may be used alone- or in combination with thenerve stimulation electrodes. For example, a catheter comprising one ormore wire, metal strips or metal foil electrodes or electrode arrays maybe used. The catheter may comprise, for example, a balloon, which may beinflated with air or liquid to press the electrodes firmly against avessel wall that lays adjacent the phrenic nerve.

Phrenic nerve stimulation electrodes may be oriented in any fashionalong the catheter device, including longitudinally or transversely.Various techniques such as ultrasound, fluoroscopy and echocardiographymay be used to facilitate positioning of the electrodes. If desired ornecessary, avoidance of obstruction of blood flow may be achieved withnotched catheter designs or with catheters which incorporate one or moretunnels or passageways.

In another embodiment, breathing regulator 40 may comprise a connector,which interfaces with a patients respirator, and sends a logic signal toactivate or deactivate the respirator to control breathing during vagaland/or cardiac stimulation and/or destimulation.

FIG. 2 shows one embodiment of the present invention at 200. In thisembodiment, the elements named above may be combined or connected to acontrol unit along with other components. Unit 200 may be used tocoordinate the various elements.

Unit 200 may incorporate a controller as described above or any suitableprocessor 230. For example, the processor may process sensed bloodinformation from sensor 205. The controller may store and/or processsuch information before, during and/or after a medical procedure. Forexample, the patients oxygen concentration or blood pressure may besensed, stored and processed prior to and during surgery.

Unit 200 may also incorporate a nerve stimulator. For example, FIG. 2shows an electrode for nerve stimulation at 210. Electrodes used tostimulate a nerve such as the vagal nerve may be, for example,non-invasive, e.g., clips, or invasive, e.g., needles or probes. Theapplication of an electrical stimulus to the right or left vagal nervemay include, but is not limited to bipolar and/or monopolar techniques.Different electrode positions are accessible through various accessopenings, for example, in the cervical or thorax regions. Nervestimulation electrodes 210 may be positioned through a thoracotomy,sternotomy, endoscopically through a percutaneous port, through a stabwound or puncture, through a small incision in the neck or chest,through the internal jugular vein, the esophagus, the trachea, placed onthe skin or in combinations thereof. Electrical stimulation may becarried out on the right vagal nerve, the left vagal nerve or to bothnerves simultaneously or sequentially. The present invention may includevarious electrodes, catheters and electrode catheters suitable for vagalnerve stimulation to temporarily stop or slow the beating heart alone orin combination with other heart rate inhibiting agents.

Nerve stimulation electrodes 210 may be endotracheal, endoesophageal,intravascular, transcutaneous, intracutaneous, patch-type, balloon-type,cuff-type; basket-type, umbrella-type, tape-type, screw-type, barb-type,metal, wire, or suction-type electrodes. Guided or steerable catheterdevices comprising electrodes may be used alone or in combination withthe nerve stimulation electrodes 210. For example, a catheter comprisingone or more wire, metal strips or metal foil electrodes or electrodearrays maybe inserted into the internal jugular vein to make electricalcontact with the wall of the internal jugular vein, and thus stimulatethe vagal nerve adjacent to the internal jugular vein. Access to theinternal jugular vein may be via, for example, the right atrium, theright atrial appendage, the inferior vena cava or the superior venacava. The catheter may comprise, for example, a balloon, which may beinflated with air or liquid to press the electrodes firmly against thevessel wall. Similar techniques may be performed by insertion of acatheter type device into the trachea or esophagus. Additionallytracheal tubes and esophageal tubes comprising electrodes may be used.

Nerve stimulation electrodes 210 may be oriented in any fashion alongthe catheter device, including longitudinally or transversely. Varioustechniques such as ultrasound, fluoroscopy and echocardiography may beused to facilitate positioning of the electrodes. If desired ornecessary, avoidance of obstruction of blood flow may be achieved withnotched catheter designs or with catheters which incorporate one or moretunnels or passageways.

In one embodiment of the present invention the location of theelectrodes 210 is chosen to elicit maximum bradycardia effectivenesswhile minimizing current spread to adjacent tissues and vessels and toprevent the induction of post stimulation tachycardia. Furthermore, anon-conductive material such as configurations to shield them from thesurrounding tissues and vessels, while exposing their confronting edgesand surfaces for positive contact with the vagal nerve or selectedtissues.

Unit 200 may also incorporate a cardiac stimulator. For example, FIG. 2shows a electrode for stimulation of the heart at 220. Cardiacelectrodes 220 used to stimulate the heart may be, for example,non-invasive, e.g., clips, or invasive, e.g. needles or probes.Electrodes 220 may be positioned through a thoracotomy, sternotomy,endoscopically through a peutaneous port, through a stab wound orpuncture, through a small incision in the chest, placed on the chest orin combinations thereof. The present invention may also use variouselectrodes, catheters and electrode catheters and to pacing the heart,e.g., epicardial, patch-type, intravascular, balloon-type, basket-type,umbrella-type tape-type electrodes, suction-type, pacing electrodes,endotracheal electrodes, endoesophageal electrodes, transcutaneouselectrodes, intracutaneous electrodes, screw-type electrodes, barb-typeelectrodes, bipolar electrodes, monopolar electrodes, metal electrodes,wire electrodes and cuff electrodes, Guided or steerable catheterdevices comprising electrodes may be used alone or in combination withthe electrodes. Controller 230 may be used to gather information fromnerve stimulation electrodes 210 and cardiac stimulation electrodes 220.Controller 230 may also be used to control the stimulation levels andstimulation duration from nerve stimulation electrodes 210 and cardiacstimulation electrodes 220. Controller 230 may also gather and processinformation from sensor 205. This information may be used toadjust-stimulation levels and stimulation times from nerve stimulationelectrodes 210 and cardiac stimulation electrodes 220.

Unit 200 may incorporate one or more switches to facilitate regulationof the various components by the surgeon. One example of such a switchis shown as foot pedal 250. The switch may also be, for example, a handswitch, or a voice-activated switch comprising voice-recognitiontechnologies. The switch may be incorporated in or on one of thesurgeons instruments, such as surgical site retractor, or any otherlocation easily and quickly accessed by the surgeon. Unit 200 may alsoinclude a display 260. Unit 200 may also include other means ofindicating the status of various components to the surgeon such as anumerical display, gauges, a monitor display or audio feedback. Unit 200may also include one or more visual and/or audible signals used toprepare a surgeon for the start or stop of nerve stimulation and/orcardiac stimulation.

FIG. 3 shows a flow diagram of one embodiment of the present invention.The patient is prepared for a medical procedure at 500. Once the patientis prepared, the initial state of cerebral blood circulation is measured(Block 505). Such measurements may include for example blood flow,oxygen concentration, carbon dioxide concentration, etc. The initialstate of cerebral blood circulation is then used as a gauge to comparewith the state of cerebral blood circulation during the procedure.

At Block 510, a nerve that controls the beating of the heart isstimulated. Such a nerve may be for example a vagal nerve. At Block 510,one or more of a variety of pharmacological agents or drugs may bedelivered. These drugs may produce reversible asystole of a heart whilemaintaining the ability of the heart to be electrically paced.

A variety of pharmacological agents or drugs may also be delivered atother times during the procedure 500. These drugs may also producereversible asystole of a heart while maintaining the ability of theheart to be electrically paced. Other drugs may be administered for avariety of functions and purposes as described below. Drugs may bedelivered at any appropriate time during the medical procedure, forexample, at the beginning of the procedure, intermittently during theprocedure, continuously during the procedure or following the procedure.

Drugs, drug formulations or compositions suitable for administration toa patient during a medical procedure may include a pharmaceuticallyacceptable carrier or solution in an appropriate dosage. There are anumber of pharmaceutically acceptable carriers that may be used fordelivery of various drugs, for example, via direct injection, oraldelivery suppository delivery, transdermal delivery, epicardial deliveryand/or inhalation delivery. Pharmaceutically acceptable carriers includea number of solutions, preferably sterile, for example, water, saline.Ringers solution and/or sugar solutions such as dextrose in water orsaline. Other possible carriers that may be used include sodium citrate,citric acid, amino acids, lactate, mannitol, maltose, glycerol, sucrose,ammonium chloride, sodium chloride, potassium chloride, calciumchloride, sodium lactate, and/or sodium bicarbonate. Carrier solutionsmay or may not be buffered.

Drug formulations or compositions may include antioxidants orpreservatives such as ascorbic acid. They may also be in apharmaceutically acceptable form for parenteral administration, forexample to the cardiovascular system, or directly to the heart, such asintracoronary infusion or injection. Drug formulations or compositionsmay comprise agents that provide a synergistic effect when administeredtogether. A synergistic effect between two or more drugs or agents mayreduce the amount that normally is required for therapeutic delivery ofan individual drug or agent. Two or more drugs may be administered, forexample, sequentially or simultaneously. Drugs may be administered viaone or more bolus injections and/or infusions or combinations thereof.The injections and/or infusions may be continuous or intermittent. Drugsmay be administered, for example, systemically or locally, for example,to the heart, to a coronary artery and/or vein, to a pulmonary arteryand/or vein, to the right atrium and/or ventricle, to the left atriumand/or ventricle to the aorta, to the AV node, to the SA node, to anerve and/or to the coronary sinus. Drugs may be administered ordelivered via intravenous, intracoronary and/or intraventricularadministration in a suitable carrier. Examples of arteries that may beused to deliver drugs to the AV node include the AV node artery, theright coronary artery, the right descending coronary artery, the leftcoronary artery, the let anterior descending coronary artery and Kugel'sartery. Drugs may be delivered systemically, for example, via oral,transdermal, intranasal suppository or inhalation methods. Drugs alsomay be delivered via a pill, a spray, a cream, an ointment or amedicament formulation.

Drugs may be delivered via a drug delivery device that may comprise acatheter, such as a drug delivery catheter or a guide catheter, a patch,such as a transepicardial patch that slowly releases drugs directly intothe myocardium, a cannula, a pump and/or a hypodermic needle and syringeassembly. A drug delivery catheter may include an expandable member,e.g., a low-pressure balloon, and a shaft having a distal portion,wherein the expandable member is disposed along the distal portion. Acatheter for drug delivery may comprise one or more lumens and may bedelivered endovascularly via insertion into a blood vessel, e.g., anartery such as a femoral, radial, subclavian or coronary artery. Thecatheter can be guided into a desired position using various guidancetechniques, e.g., flouroscopic guidance and/or a guiding catheter orguide wire techniques. Drugs may be delivered via an iontophoretic drugdelivery device placed on the heart. In general, the delivery of ionizeddrugs may be enhanced via a small current applied across two electrodes.Positive ions may be introduced into the tissues from the positive pole,or negative ions from the negative pole. The use of iontophoresis maymarkedly facilitate the transport of certain ionized drug molecules. Forexample, lidocaine hydrochloride may be applied to the heart via a drugpatch comprising the drug. A positive electrode could be placed over thepatch and current passed. The negative electrode would contact the heartor other body part at some desired distance point to complete thecircuit. One or more of the electrodes may also be used as nervestimulation electrodes 210 or as cardiac stimulation electrodes 220.

The two divisions of the autonomic nervous system that regulate theheart have opposite functions. First, the adrenergic or sympatheticnervous system increases heart rate by releasing epinephrine andnorepinephrine. Second, the parasympathetic system also known as thecholinergic nervous system or the vagal nervous system decreases heartrate by releasing acetylcholine. Catecholamines such as norepinephrine(also called noradrenaline) and epinephrine (also called adrenaline) areagonists for beta-adrenergic receptors. An agonist is a stimulantbiomolecule or agent that binds to a receptor.

Beta-adrenergic receptor blocking agents compete with beta-adrenergicreceptor stimulating agents for available beta-receptor sites. Whenaccess to beta-receptor sites are blocked by receptor blocking agents,also known as beta-adrenergic blockade, the chronotropic or heart rate,inotropic or contractility, and vasodilator responses to receptorstimulating agents are decreased proportionately. Therefore,beta-adrenergic receptor blocking agents are agents that are capable ofblocking beta-adrenergic receptor sites.

Since beta-adrenergic receptors are concerned with contractility andheart rate, stimulation of beta-adrenergic receptors, in general,increases heart rate, the contractility of the heart and the rate ofconductor of electrical impulses through the AV node and the conductionsystem.

Drugs, drug formulations and/or drug compositions that may be usedaccording to this invention may include any naturally occurring orchemically synthesized (synthetic analogues) beta-adrenergic receptorblocking agents. Beta-adrenergic receptor or □-adrenegic blocking agentsare also known as beta-blockers or □-blockers and as class IIantiarrhythmics.

The term “beta-blocker” appearing herein may refer to one or more agentsthat antagonize the effects of beta-stimulating catecholamines byblocking the catecholamines ines from binding to the beta-receptors.Examples of beta-blockers include, but are not limited to a acebutolol,alprenolol, atenolol, betantolol, betaxolol, becantolol, bisoprolol,carterolol, celiprblol, chlorthalidone, esmolol, labetalol, metoprolol,nadolol, penbutolol, pindolol, propranolol, oxprenolol, sotalol,teratolo, timolol and combinations, mixtures and salts thereof.

The effects of administered beta-blockers may be reversed byadministration of beta-receptor agonists, e.g., dobutamine orisoproterenol.

The parasympathetic or cholinergic system participates in control ofheart rate via the sinoatrial (SA) node, where it reduces heart rate.Other cholinergic effects include inhibition of the AV node and aninhibitory effect on contractile force. The cholinergic system actsthrough the vagal nerve to release acetylcholine, which, in turn,stimulates cholinergic receptors. Cholinergic receptors are also knownas muscarinic receptors. Stimulation of the cholinergic receptorsdecreases the formation of CAMP. Stimulation of cholinergic receptorsgenerally has an opposite effect on heart rate compared to stimulationof beta-adrenergic receptors. For example, beta-adrenergic stimulationincreases heart rate, whereas cholinergic stimulation decreases it. Whenvagal tone is high and adrenergic tone is low, there is a markedslowing, of the heart (sinus bradycardia). Acetylcholine effectivelyreduces the amplitude, rate of increase and duration of the SA nodeaction potential. During vagal nerve stimulation, the SA node does notarrest. Rather, pacemaker function may shift to cells that fire at aslower rate. In addition, acetylcholine may help open certain potassiumchannels thereby creating an outward flow of potassium ions andhyperpolarization. Acetylcholine also slows conduction through the AVnode.

Drugs, drug formulations and/or drug compositions that may be usedaccording to this invention may include any naturally occurring orchemically synthesized (synthetic analogues) cholinergic agent. The term“cholinergic agent” appearing herein may refer to one or morecholinergic receptor modulators, or agonists. Examples of cholinergicagents include, but are not limited to, acetylcholine, carbachol(carbamyl choline chloride), bethanechol, methacholine, arecoline,norarecoline and combinations, mixtures and/or salts thereof.

Drugs, drug formulations and/or drug compositons that may be usedaccording to this invention may include any naturally occurring orchemically synthesized cholinesterase inhibitor. The term“cholinesterase inhibitor” appearing herein may refer to one or moreagents that prolong the action of acetylcholine by inhibiting itsdestruction or hydrolysis by cholinesterase. Cholinesterase inhibitorsare also known as acetylcholinesterase inhibitors. Examples ofcholinesterase inhibitors include, but are not limited to, edrophonium,neostigmine, neostigmine methylsulfate; pyridostigmine, tacrine andcombinations, mixtures and/or salts thereof.

There are ion-selective channels within certain cell membranes. Theseion selective channels include calcium channels, sodium channels and/orpotassium channels. Therefore, other drugs, drug formulations and/ordrug compositions that may be used according to this invention mayinclude any naturally occurring or chemically synthesized calciumchannel blocker. Calcium channel blockers inhibit the inward flux ofcalcium ions across cell membranes of arterial smooth muscle cells andmyocardial cells. Therefore, the term “calcium channel blocker”appearing herein may refer to one or more agents that inhibit or blockthe flow of calcium ions across a cell membrane. The calcium channel isgenerally concerned with the triggering of the contractile cycle.Calcium channel, blockers are also known as calcium ion influxinhibitors, slow channel blockers, calcium ion antagonists, calciumchannel antagonist drugs and as class IV antiarrhythmics. A commonlyused calcium channel blocker is verapamil.

Administration of a calcium channel blocker, e.g., verapamil, generallyprolongs the effective refractory period within the AV node and slows AVconduction in a rate-related manner, since the electrical activitythrough the AV node depends significantly upon the influx of calciumions through the slow channel. A calcium channel blocker has the abilityto slow a patients heart rate, as well as produce AV block. Examples ofcalcium channel blockers include, but are not limited to, amiloride,amlodipine, bepridil, diltiazem, felodipine, isradipine, mibefradil,nicardipine, nifedipine (dihydropyridines), nickel, nimodinpine,nisoldipine, nitric oxide (NO), norverapamil and veraparhil andcombinations, mixtures and/or salts thereof. Verapamil and diltiazem arevery effective at inhibiting the AV node, whereas drugs of thenifedipine family have a lesser inhibitory effect on the AV node. Nitricoxide (NO) indirectly promotes calcium channel closure. NO may be usedto inhibit contraction. NO may also be used to inhibit sympatheticoutflow, lessen the release of norepinephrine, cause vasodilation,decrease heart rate and decrease contractility. In the SA node,cholinergic stimulation leads to formation of NO.

Other drugs, drug formulations and/or drug compositions that may be usedaccording to this invention may include any naturally occurring orchemically synthesized sodium channel blocker. Sodium channel blockersare also known as sodium channel inhibitors, sodium channel blockingagents, rapid channel blockers or rapid channel inhibitors.Antiarrhythmic agents that inhibit or block the sodium channel are knownas class I antiarrhythmics, examples include, but are not limited to,quinidine and quinidine-like agents, lidocaine and lidocaine-likeagents, tetrodotoxin, encainide, flecainid and combinatons, mixturesand/or salts thereof. Therefore, the term “sodium channel blocker”appearing herein may refer to one or more agents that inhibit or blockthe flow of sodium ions across a cell membrane or remove the potentialdifference across a cell membrane. For example, the sodium channel mayalso be totally inhibited by increasing the extracellular potassiumlevels to depolarizing hyperkalemic values, which remove the potentialdifference across the cell membrane. The result is inhibition of cardiaccontraction with cardiac arrest (cardioplegia). The opening of thesodium-channel (influx of sodium) is for swift conduction of theelectrical impulse throughout the heart.

Other drugs, drug formulations and/or drug compositions that may be usedaccording to this invention may include any naturally occurring orchemically synthesized potassium channel agent. The term “potassiumchannel agent” appearing herein may refer to one or more agents thatimpact the flow of potassium ions across the cell membrane. There aretwo major types of potassium channels. The first type of channel isvoltage-gated and the second type is ligand-gated.Acetylcholine-activated potassium channels, which are ligand-gatedchannels, open in response to vagal stimulation and the release ofacetylcholine. Opening of the potassium channel causeshyperpolarization, which decreases the rate at which the activationthreshold is reached. Adenosine is one example of a potassium channelopener. Adenosine slows conduction through the AV node. Adenosine, abreakdown product of adenosine triphosphate inhibits the AV node andatria. In, atrial tissue, adenosine causes the shortening of the actionpotential duration and causes hyperpolarization. In the AV node,adenosine has similar effects and also decreases the action potentialamplitude and the rate of increase of the action potential. Adenosine isalso a direct vasodilator by its actions on the adenosine receptor onvascular smooth muscle cells. In addition, adenosine acts as a negativeneuromodulator, thereby inhibiting release of norepinephrine. Class IIIantiarrhythmic agents also known as potassium channel inhibitorslengthen the action potential duration and refractoriness by blockingthe outward potassium channel to prolong the action potential.Amiodarone and d-sotalol are both examples of class III antiarrhythmicagents.

Potassium is the most common component in cardioplegic solutions. Highextracellular potassium levels reduce the membrane resting potential.Opening of the sodium channel, which normally allows rapid sodium influxduring the upstroke of the action potential, is therefore inactivatedbecause of a reduction in the membrane resting potential. The presentinvention may be combined with conventional CPB, the induced asystole asdescribed by this invention may serve as a substitute for conventionalcardioplegic arrest. For example, the combination of drugs and vagalstimulation may be used as a cardioplegic agent in a variety of medicalprocedures.

Drugs, drug formulations and/or drug compositions that may be usedduring according to this invention may comprise one or more of anynaturally occurring or chemically synthesized beta-blocker, cholinergicagent, cholinesterase inhibitor, calcium channel blocker, sodium channelblocker, potassium channel agent, adenosine, adenosine receptor agonist,adenosine deaminase inhibitor, dipyridamole, monoamine oxidaseinhibitor, digoxin, digitalis, lignocaine, bradykinin agents,serotoninergic agonist, antiarrythmic agents, cardiac glycosides, localanesthetics and combinations or mixtures thereof. Digitalis and digoxinboth inhibit the sodium pump. Digitalis is a natural inotrope derivedfrom plant material, while digoxin is a synthesized inotrope.Dipyridamole inhibits adenosine deaminase, which breaks down adenosine.Drugs, drug formulations and/or drug compositions capable of reversiblysuppressing autonomous electrical conduction at the SA and/or AV node,while still allowing the heart to be electrically paced to maintaincardiac output may be used according to this invention.

In one embodiment, thee cardiac asystole produced in accordance with theresent invention is reversible e.g., chemically such as by theadministration of atropine or by natural forces. Beta-adrenergicstimulation or administration of calcium solutions may be used toreverse the effects of a calcium channel blocker such as verapamil.Agents that promote heart rate and/or contraction may be used in apreferred embodiment of the present invention. For example, dopamine, anatural catbcliplamine, is known to increase contractility. Positiveinotropes are agents that specifically increase the force of contractionof the heart. Glucagon, a naturally occurring hormone, is known toincrease heart rate and contractility. Glucagon may be used to reversethe effects of a beta-blocker since its effects bypass the betareceptor. Forskolin is known to increase heart rate and contractility.As mentioned earlier epinephrine and norepiriephrine naturally increaseheart rate and contractility. Thyroid hormone, phosphodiesteraseinhibitors and prostacyclin, a prostaglandin are also known, to increaseheart rate and contractility. In addition, methylxanthines are known toprevent adenosine from interacting with its cell receptors.

Typically, vagal nerve stimulation prevents the heart from contracting.This non-contraction must then be followed by periods. Without vagalnerve stimulation during which the heart is allowed to contract, andblood flow is restored throughout the body. At block 517, the state ofcerebral blood circulation may be monitored. This monitoring may occurat specific points during the procedure, for example, as shown at block517. Alternatively, monitoring may occur continuously. If cerebral bloodcirculation is sufficient, then all or a portion of the medicalprocedure may be carried out (Block 520). However, if the state ofcerebral blood circulation is not sufficient, then a signal may indicatethat the state of blood circulation to the brain is insufficient. If thesensor indicates that the state of blood circulation is insufficient,the surgeon may proceed to block 530, where the nerve stimulation isceased an the heart is allowed to contract. The cardiac stimulator maybe used to cause the heart to contract. Alternatively, unit 200 mayautomatically proceed to Block 530 to cease nerve stimulation. Inaddition, Unit 200 may automatically begin cardiac stimulation.

The state of cerebral blood circulation sensed by sensor 5 may becommunicated to the surgeon by a number of suitable means. For example,the ambient blood flow may be indicated on a display or monitor. Avisual or audio signal may indicate when the level of cerebral bloodflow reaches a certain level, e.g. when blood flow is insufficient.Alternatively, the system of the present invention may “lock” thecontrols of the vagal stimulator in an “off” state when cerebral bloodflow reaches a predetermined condition, thereby indicating that bloodflow is insufficient. The system may then release the controls when thestate of cerebral blood circulation sensed by the sensor is againsufficient.

Additionally, the amount of vagal nerve stimulation used may be adjustedbased on the output of the sensor 5. For example, the level ofstimulation may be lowered or the duration of stimulation may be loweredif the sensor indicates that cerebral blood circulation at 517 isinsufficient. This adjustment may be automatic or may be controlled bythe surgeon.

At Block 520, a medical procedure may be performed or begun. Such aprocedure may be for example surgery on the heart. Alternatively, theprocedure may be surgery performed on another organ of the body.

The term “medical procedure” may mean any one or more medical orsurgical procedures such as, for example cardiac surgery, performed withor without cardiopulmonary bypass (CPB) circuits, heart valve repair,heart valve replacement, MAZE procedures, transmyocardialrevascularization (TMR), CABG procedures, anastomosis procedures,non-surgical procedures, fluoroscpic procedures, beating heart surgery,vascular surgery, neurosurgery, brain surgery, electrophysiologyprocedures diagnostic and therapeutic procedures, ablation procedures,ablation of arrhythmias, endovascular procedures, treatment of theliver, spleen, heart, lungs, and major blood vessels, aneurysm repair,imaging procedures of the heart and great vessels, CAT scans or MRIprocedures, pharmacological therapies, drug delivery procedures, genetherapies, cellular therapies, cancer therapies, radiation therapies,genetic, cellular, tissue and/or organ manipulation or transplantationprocedures, coronary angioplasty procedures, placement or delivery ofcoated or noncoated stents, atherectomy procedures, atheroscleroticplaque manipulation and/or removal procedures, procedures where bleedingneeds to be precisely controlled, procedures that require precisecontrol of cardiac motion and/or bleeding.

When the medical procedure comprises one or more medical devices, e.g.,coated stents, these devices may be coated with one or more radioactivematerials and/or biological agents such as, for example, ananticoagulant agent, an antithrombotic agent, a clotting agent, aplatelet agent, an anti-inflammatory agent an antibody, an antigen, animmunoglobulin, a defense agent, an enzyme, a hormone, a growth factor,a neurotransmitter, a cytokine, a blood agent, a regulatory agent, atransport agent, a fibrous agent, a protein, a peptide, a proteoglycan,a toxin, an antibiotic agent, an antibacterial agent, an antimicrobialagent, a bacterial agent or component, hyaluronic acid a polysaccharide,a carbohydrate, a fatty acid, a catalyst, a drug, a vitamin, a DNAsegment, a RNA segment, a nucleic acid, a lectin, an antiviral agent, aviral agent or component, a genetic agent, a ligand and a dye (whichacts as a biological ligand). Biological agents may be found in nature(naturally occurring) or may be chemically synthesized.

The medical procedure may be non-invasive, minimally invasive and/orinvasive. The medical procedure-may entail a port-access approach, apartially or totally endoscopic approach, a sternotomy approach or athoracotomy approach. The medical procedure may include the use ofvarious mechanical stabilization devices or techniques as well asvarious robotic or imaging systems.

In one method, the heart may be temporarily slowed or intermittentlystopped for short periods of time to permit the surgeon to accomplishthe required surgical task and yet still allow the heart itself tosupply blood circulation to the body. For example, stimulation of thevagus nerve in order to temporarily and intermittently slow or stop theheart is described in U.S. Pat. No. 6,006,134 entitled “Method andDevice for Electronically Controlling the Beating of a Heart UsingVenous Electrical Stimulation of Nerve Fibers”, Dec. 21, 1999, to Hilland Junkman. This patent is assigned to Medtronic, Inc. and isincorporated herein by reference.

During this medical procedure, the state of cerebral blood circulationmay be monitored constantly or intermittently as described above. Anassessment, for example, of the amount of blood flowing to the brain mayagain be taken at block 525. If the state of cerebral blood circulationis sufficient the physician may continue with the medical procedure thatis in progress. However, if the state of cerebral blood circulation isnot sufficient, then the sensor 5 may indicate that blood circulation tothe brain is insufficient. If the sensor indicates that bloodcirculation is insufficient, the surgeon may proceed to Block 530, wherethe nerve stimulation is ceased. The heart will therefore be allowed tocontract and thus blood will again be allowed to flow to the brain andvital organs. The cardiac stimulator maybe used to cause the heart tocontract. Alternatively, unit 200 may automatically proceed to Block 530to cease nerve stimulation. In addition, Unit 200 may automaticallybegin cardiac stimulation. Additionally the amount of vagal nervestimulation used may be adjusted based on the output of the sensor 5.For example, the level of stimulation may be lowered or the duration ofstimulation may be lowered if the sensor indicates that cerebral bloodcirculation at 525 is insufficient.

After a time, the medical procedure or one phase of the procedure iscompleted at 520. After some phase of the medical procedure isperformed, cardiac contractions are allowed to occur (Block 530).Cardiac contractions may need to occur intermittently during theprocedure to ensure adequate blood flow. In one embodiment, thestimulation from the nerve stimulator 10 is stopped or slowed enough toallow the heart to contract. For example, the vagal nerve stimulation isremoved, thereby allowing cardiac contractions to occur.

In another embodiment, the heart may be stimulated to ensure thatcardiac contractions occur (Block 535). For example, cardiac stimulator20 may be used to apply pacing pulses to the heart to encourage theheart to contract normally. In particular, the pacing pulses may beapplied to the ventricle as is well known in the field. Additionally,the amount of cardiac stimulation used may be adjusted based on theoutput of the sensor 5. For example, the level of stimulation may, beincreased or the duration of stimulation may be increased if the sensorindicates that cerebral blood circulation at 525 is insufficient.

The present invention permits the heart to be stilled or quiescent forselected and controllable periods of time in order to permit a medicalprocedure to be performed. While such a period of stillness orquiescence is desired, it must not last too long, otherwise insufficientblood and oxygen is delivered to organs. Thus, it is necessary to havethe periods when the heart is beating (Blocks 530, 535).

The state of cerebral blood circulation, for example, sensed by sensor 5while the heart is beating may be communicated to the surgeon by anumber of suitable means. For example, ambient blood flow may beindicated on a display or monitor. A visual or audio signal may indicatewhen the level of cerebral blood flow reaches a certain level, e.g. whenblood flow is insufficient. Alternatively, the system of the presentinvention may “lock” the controls of the cardiac stimulator in an “on”state when the state of cerebral blood circulation reaches apredetermined condition, thereby indicating that blood circulation isinsufficient. The system may then release the controls when the state ofblood circulation sensed by the sensor is again sufficient.

If additional medical procedures or additional stages of medicalprocedures need to be performed, the heart may again be stilled usingthe methods of stilling the heart described above. Therefore from Block530 or Block 535, the method may be repeated (as in the loop designatedby 540). For example, the heart may again be prevented from contractingby stimulation of the vagal nerve (510). Additional drugs may bedelivered or the drugs previously administered may continue to beadministered.

This cycle may be repeated until the procedure, such as the surgery, iscompleted. As the cycle continues sensor 5 enables monitoring of thestate of blood circulation and, if necessary, appropriate adjustment ofnerve stimulation and cardiac stimulation to ensure sufficient bloodcirculation.

For example, the surgical procedure at 520 may require several stitchesto be made by the surgeon. The surgeon may stimulate the vagal nerve, at510 to stop the heart. Then the surgeon may make the first stitch at520. The surgeon may then reduce or halt stimulation at 530 and allowthe heart to contract. The surgeon may also pace the heart at 535. Thenat 540, the surgeon may return to 510 to inhibit contractions of theheart. At 520, the surgeon will then make the second stitch. Thisprocess may be repeated (the loop designated by 540 may be repeated)until all the required stitches have been made. Meanwhile, the state ofblood circulation is monitored continuously or, for example at Blocks517 and 525 by sensor 5. The procedure may proceed uninterrupted if thestate of blood circulation remains sufficient.

If required, after the procedure is completed, step 535 may be performeduntil the heart is beating normally. Step 545 may be continued until,the physician is satisfied that the heart is beating normally and thestate of blood circulation has reached an acceptable level.

FIG. 4 is a timeline showing the relationship of a sensor, a nervestimulator and a cardiac stimulator in one embodiment of the presentinvention.

Point 610 indicates a point before the medical procedure has begun. Atthis point 610, both nerve stimulation and cardiac stimulation are off.At point 610, the heart is beating regularly. The patients state ofcerebral blood circulation, for example, may be measured by sensor 5 atpoint 610. Thus sensor 5 may be turned on at point 610.

Then nerve stimulation is turned on to inhibit beating of the heart.During phase 601, the vagal nerve stimulation is on and the cardiacstimulation is off. This is the condition of the two types ofstimulation at step 520 described above. In one embodiment, shown inFIG. 3 sensor 5 is on throughout the entire procedure. Alternatively,sensor 5 may be turned on during phase 601 to check the state ofcerebral blood circulation (as described at Block 517).

Point 611 is a representative point during phase 601. At point 611 thecontractions of the heart are stilled or substantially slowed. Also, atpoint 611, the current state of cerebral blood-circulation may bedetermined (as described at Blocks 517 and 525). If the state ofcerebral blood circulation at point 611 is sufficient, then the medicalprocedure can proceed (as described at Block 520). However, if the stateof cerebral blood circulation is not sufficient at point 611, sensor 5may provide a signal indicating that the state of cerebral bloodcirculation is insufficient. The surgeon may then proceed immediately tophase 602. Alternatively, control unit 200 may automatically proceed tophase 602 after providing the signal.

Additionally, the amount of vagal stimulation used may be adjusted basedon the output of the sensor 5. For example, the level of stimulation maybe decreased or the duration of stimulation may be decreased if thesensor indicates that the state of blood circulation, at point 611 isinsufficient.

During phase 602 the vagal stimulation is turned off (as described atstep 530) and the cardiac stimulation may be turned on (as described at535). Point 612 is a representative point during phase 602. At point612, the contractions are allowed and/or may be induced. In oneembodiment, sensor 5 is still on during phase 602. Alternatively, sensor5 may be turned on during phase 602 to check the state of bloodcirculation to the brain.

Additionally, the amount of cardiac stimulation used may be adjustedbased on the output of the sensor 5. For example, the level ofstimulation may be increased or the duration of stimulation may beincreased if the sensor indicates that cerebral blood circulation atpoint 612 is insufficient.

During phase 603, the vagal nerve stimulation is again turned on and thecardiac stimulation is turned off. Also, during phase 603, sensor 5 maystill be on. The amount or duration of vagal stimulation during phase603 may be different than the amount or duration of vagal stimulationduring phase 601, based on the data gathered from sensor 5 during phase601. Alternatively, the current state of cerebral blood circulation mayagain be determined during phase 603 (as described at Block 525). Point613 is a representative point during phase 603. If the state of bloodcirculation at point 613 is sufficient, then the medical procedure canproceed (as described in step 520). However, if the state of bloodcirculation is not sufficient at point 611, sensor 5 may provide asignal indicating that blood circulation is insufficient. The surgeonmay then proceed immediately to phase 602. Alternatively control unit200 may automatically proceed to phase 602 after providing the signal.Additionally, the amount of vagal stimulation used may again be adjustedbased on the output of the sensor 5.

During phase 604 the vagal stimulation is again turned off and thecardiac stimulation may again be turned on. The amount or duration ofcardiac stimulation during phase 604 may be different than the amount orduration of cardiac stimulation during phase 602, based on the datagathered from sensor 5 during the previous phases.

The method of the present invention may be repeated as necessary until apoint is reached, represented by point 615, when the necessary medicalprocedures are completed. At this point 615, nerve stimulation is offalthough cardiac stimulation may be left on in order to pace the heartto its normal rhythm. At point 615, the state of cerebral bloodcirculation may be checked for a final time (as described at 545).

It will be appreciated by those skilled in the art that while theinvention has been described above in connection with particularembodiments and examples, the invention is not necessarily so limited,and that numerous other embodiments examples, uses, modifications anddepartures from the embodiments, examples and uses are intended to beencompassed by the claims attached hereto.

1-8. (canceled)
 9. A method for controlling a heart beat during amedical procedure, comprising: sensing a first gas level in a body;stimulating a first nerve to inhibit beating of a heart; performing atleast one step of the medical procedure; sensing a second gas levelwhile performing the medical procedure; stopping stimulation of thefirst nerve to allow beating of the heart when the second gas level isless than the initial gas level.
 10. The method of claim 9 wherein thegas level is sensed for at least one of the characteristics selectedfrom the group consisting of presence of oxygen, concentration ofoxygen, presence of carbon dioxide, and concentration of carbon dioxide.11. The method of claim 9 further comprising stimulating the heart witha cardiac stimulator to cause beating of the heart when the second gaslevel is less than the first gas level.
 12. The method of claim 9wherein the first gas level and second gas level are sensed in cerebralblood flow.
 13. The method of claim 9 further comprising providing analert signal when the second value is less than the first value.
 14. Themethod of claim 12 wherein the alert signal is selected from the groupconsisting of: a visual signal, a flashing light, an audible signal, anda beeping tone.
 15. The method of claim 9 wherein the medical procedureis started after sensing the first gas level, and wherein the second gaslevel is sensed during the medical procedure.
 16. A method forperforming a medical procedure, comprising: sensing a characteristic ofa bodily tissue or fluid via a sensor at a first value; sending a firstsignal related to the sensed characteristic at a first value; modifyingthe beating of a heart via a nerve stimulator in response to the firstsignal; performing at least one step of the medical procedure; sensingthe characteristic via the sensor at a second value; sending a secondsignal related to the sensed characteristic at a second value; andmodifying the beating of the heart via a cardiac stimulator in responseto the second signal.
 17. The method of claim 16 wherein modifying thebeating of the heart via a nerve stimulator is performed automatically.18. The method of claim 16 wherein modifying the beating of the heartvia a nerve stimulator is performed manually.
 19. The method of claim 16wherein modifying the beating of the heart via a cardiac stimulator isperformed automatically.
 20. The method of claim 16 wherein modifyingthe beating of the heart via a cardiac stimulator is performed manually.21. The method of claim 16 further comprising the delivery of a drugduring the medical procedure.
 22. The method of claim 21 wherein thedrug is delivered via a drug delivery means.
 23. The method of claim 22wherein the drug delivery means is selected from the group consisting ofa spray, a cream, an ointment, a medicament, a pill, a patch, acatheter, a cannula, a needle and syringe, a pump, and an iontophoreticdrug delivery device.
 24. The method of claim 21 wherein the drug isselected from the group consisting of a beta-blocker, a cholinergicagent, a cholinesterase inhibitor, a calcium channel blocker, a sodiumchannel blocker, a potassium channel agent, adenosine, an adenosinereceptor agonist, an adenosine deaminase inhibitor, dipyridamole, amonoamine oxidase inhibitor, digoxin, digitalis, lignocaine, abradykinin agent, a serotoninergic agonist, an antiarrythmic agent, acardiac glycoside, a local anesthetic, atropine, a calcium solution, anagent that promotes heart rate, an agent that promotes heartcontractions, dopamine, a catecholamine, an inotrope glucagon, ahormone, forskolin, epinephrine, norepinephrine, thyroid hormone, aphosphodiesterase inhibitor, prostacyclin, prostaglandin and amethylxanthine.
 25. The method of claim 21 wherein the drug is naturallyoccurring or chemically synthesized.
 26. The method of claim 16 whereinthe nerve stimulator modifies the beating of the heart by stimulating avagal nerve.
 27. The method of claim 16 wherein the nerve stimulatormodifies the beating of the heart by stimulating a carotid sinus nerve.28. The method of claim 16 wherein the nerve stimulator modifies thebeating of the heart by stimulating a fat pad.
 29. The method of claim16 wherein the bodily fluid is blood.
 30. The method of claim 16 whereinthe bodily tissue is cardiac tissue.
 31. The method of claim 16 whereinthe bodily tissue is a nerve.
 32. The method of claim 16 wherein thecharacteristic of a bodily tissue or fluid is a chemical characteristic.33. The method of claim 16 wherein the characteristic of a bodily tissueor fluid is a physical characteristic.
 34. The method of claim 16wherein the characteristic of a bodily tissue or fluid is aphysiological characteristic.
 35. The method of claim 16 wherein thecharacteristic of a bodily tissue or fluid is a fluid flowcharacteristic.
 36. The method of claim 16 wherein the characteristic ofa bodily tissue or fluid is a pressure characteristic.
 37. The method ofclaim 16 wherein the characteristic of a bodily tissue or fluid is atemperature characteristic.
 38. The method of claim 16 wherein thecharacteristic of a bodily tissue or fluid is an electricalcharacteristic.
 39. The method of claim 16 wherein the characteristic ofa bodily tissue or fluid is a chemical concentration.
 40. The method ofclaim 16 wherein the characteristic of a bodily tissue or fluid is aprotein or peptide.
 41. The method of claim 16 wherein thecharacteristic of a bodily tissue or fluid is a component of a metabolicprocess.
 42. The method of claim 16 wherein the characteristic of abodily tissue or fluid is a gas.
 43. The method of claim 42 wherein thegas is oxygen.
 44. The method of claim 42 wherein the gas is carbondioxide.
 45. The method of claim 16 wherein the sensor is selected fromthe group consisting of an imaging system, an electrical sensor, achemical sensor, an electromagnetic interference sensor, anelectrochemical sensor, a pressure sensor, a sound wave sensor, amagnetic sensor, an ultraviolet sensor, a visible light sensor, aninfrared sensor, a radiation sensor, a flow sensor, a temperaturesensor, a gas sensor, an optical sensor, a pH sensor, a potentiometricsensor, a fluorescence sensor and a biosensor.
 46. The method of claim16 wherein the nerve stimulator comprises one or more electrodes. 47.The method of claim 46 wherein the electrodes are selected from thegroup consisting of nerve stimulation electrodes, endotrachealelectrodes, endoesophageal electrodes, intravascular electrodes,transcutaneous electrodes, intracutaneous electrodes, balloon-typeelectrodes, basket-type electrodes, umbrella-type electrodes, tape-typeelectrodes, suction-type electrodes, screw-type electrodes, barb-typeelectrodes, bipolar electrodes, monopolar electrodes, metal electrodes,wire electrodes, patch electrodes, cuff electrodes, clip electrodes,needle electrodes and probe electrodes.
 48. The method of claim 16wherein the cardiac stimulator comprises one or more electrodes.
 49. Themethod of claim 48 wherein the electrodes are selected from the groupconsisting of cardiac stimulation electrodes, clip electrodes, needleelectrodes, probe electrodes, pacing electrodes, epicardial electrodes,patch electrodes, intravascular electrodes, balloon-type electrodes,basket-type electrodes, tape-type electrodes, umbrella-type electrodes,suction-type electrodes, endotracheal electrodes, endoesophagealelectrodes, transcutaneous electrodes, intracutaneous electrodes,screw-type electrodes, barb-type electrodes, bipolar electrodes,monopolar electrodes, metal electrodes, wire electrodes and cuffelectrodes.
 50. The method of claim 16 further comprising controlling apatients breathing via a breathing regulator.
 51. The method of claim 50wherein the breathing regulator stimulates a phrenic nerve.
 52. Themethod of claim 50 wherein the breathing regulator controls arespirator.
 53. The method of claim 50 wherein the breathing regulatorcomprises one or more electrodes.
 54. The method of claim 53 wherein theelectrodes are selected from the group consisting of nerve stimulationelectrodes, endotracheal electrodes, endoesophageal electrodes,intravascular electrodes, transcutaneous electrodes, intracutaneouselectrodes, balloon-type electrodes, basket-type electrodes,umbrella-type electrodes, suction-type electrodes, screw-typeelectrodes, tape-type electrodes, barb-type electrodes, bipolarelectrodes, monopolar electrodes, metal electrodes, wire electrodes,patch electrodes, cuff electrodes, clip electrodes, needle electrodesand probe electrodes.
 55. The method of claim 16 wherein the medicalprocedure is selected from the group consisting of a surgical procedure,a non-surgical procedure, a fluoroscopic procedure, a cardiac procedure,a vascular procedure, a neurosurgical procedure, an electrophysiologyprocedure, a diagnostic procedure, a therapeutic procedure, an ablationprocedure, an endovascular procedure, a liver procedure, a spleenprocedure, a pulmonary procedure, an aneurysm repair, an imagingprocedure, a CAT scan procedure, a MRI procedure, a pharmacologicaltherapy, a drug delivery procedure, a biological delivery procedure, agenetic therapy, a cellular therapy, a cancer therapy, a radiationtherapy, a transplantation procedure, a coronary angioplasty procedure,a stent delivery procedure, an atherectomy procedure, a procedure thatrequires precise control of cardiac motion, a procedure that requiresprecise control of bleeding, a non-invasive procedure, a minimallyinvasive procedure, an invasive procedure, a port-access procedure, anendoscopic procedure, a sternotomy procedure, a thoracotomy procedureand a robotic procedure.
 56. A method for performing a medicalprocedure, comprising: sensing a first level of a biologicalcharacteristic in a body; stimulating a nerve to inhibit beating of aheart; performing at least one step of the medical procedure; sensing asecond level of the biological characteristic while performing themedical procedure; stopping stimulation of the nerve to allow beating ofthe heart when the second level differs from the first level by aselective amount.
 57. The method of claim 56 wherein the biologicalcharacteristic is a chemical characteristic.
 58. The method of claim 56wherein the biological characteristic is a physical characteristic. 59.The method of claim 56 wherein the biological characteristic is aphysiological characteristic.
 60. The method of claim 56 wherein thebiological characteristic is a fluid flow characteristic.
 61. The methodof claim 56 wherein the biological characteristic is a pressurecharacteristic.
 62. The method of claim 56 wherein the biologicalcharacteristic is a temperature characteristic.
 63. The method of claim56 wherein the biological characteristic is an electricalcharacteristic.
 64. The method of claim 56 wherein the biologicalcharacteristic is a chemical concentration.
 65. The method of claim 56wherein the biological characteristic is a protein or peptide.
 66. Themethod of claim 56 wherein the biological characteristic is a componentof a metabolic process.
 67. The method of claim 56 wherein thebiological characteristic is a gas.